US2016223559A1PendingUtilityA1
Tetrazine-containing compounds and synthetic methods thereof
Est. expiryFeb 2, 2035(~8.5 yrs left)· nominal 20-yr term from priority
C07D 491/06C07F 5/02B01J 31/2291C07D 409/14C07D 405/10C07H 1/00C07D 409/04B01J 31/2409B01J 2231/40C07D 257/08B01J 2540/10G01N 33/582C07D 403/06C07H 23/00B01J 31/24B01J 2531/824B01J 31/22C07F 5/022C07H 19/06
35
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Claims
Abstract
Described herein are tetrazine derivatives and efficient synthetic methods of synthesis thereof using elimination-Heck cascade reaction. Provided herein is the synthesis of conjugated tetrazines from the tetrazine derivatives. Also provided herein are methods of use of the conjugated tetrazines as fluorogenic probes for live-cell imaging.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of synthesizing a compound of Formula I:
the method comprising reacting a compound of Formula II:
with a compound of Formula III:
R 2 —X (III),
wherein the compounds of Formula II and III are reacted in the presence of a Pd catalyst and a ligand under basic conditions, and further wherein:
L 1 and L 2 are independently a bond or a covalent linker;
X is halogen;
R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a biomolecule, a dye or fluorophore;
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or a biomolecule, a dye or fluorophore; and
LG is a leaving group.
2 . The method of claim 1 , wherein LG is an electron withdrawing group.
3 . The method of claim 1 , wherein:
LG is —N 2 + , —OR 3A 2 + , —OSO 2 R 3A F, a perfluoroalkylsulfonate, a tosylate, a mesylate, a halogen; —OH 2 + , —ONO 2 , —OPO(OH) 2 , —ONO 2 , —S(R 3B R 3C ) + , —N(R 3A R 3B R C ) + , —OCOR 3A , substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy; and R 3A , R 3B and R 3C are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCCl 3 , —OCBr 3 , —OCI 3 , —OCHF 2 , —OCHC1 2 , —OCHBr 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3B and R 3C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl.
4 . The method of claim 1 , wherein the method further comprises a solvent.
5 . The method of claim 4 , wherein the solvent is an organic solvent.
6 . The method of claim 1 , wherein the method comprises an organic base.
7 . The method of claim 1 , wherein the method is conducted at a temperature of from about 25° C. to 200° C.
8 . The method of claim 1 , wherein the method is conducted using electromagnetic radiation.
9 . The method of claim 1 , wherein the method is microwave-assisted.
10 . The method of claim 9 , wherein the method is conducted at a temperature of from about 40° C. to 80° C.
11 . The method of claim 1 , wherein the method further comprises a co-catalyst.
12 . The method of claim 1 , wherein the method is a cascade reaction or one-pot procedure.
13 . The method of claim 1 , wherein the ligand is a phosphinoferrocene ligand.
14 . The method of claim 13 , wherein the ligand is 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene.
15 . The method of claim 1 , wherein the catalyst is Pd 2 (dba) 3 .
16 . The method of claim 6 , wherein the base is trimethylamine or dicyclohexylmethylamine.
17 . The method of claim 1 , wherein the compound of Formula I is a 3-substituted-6-alkenyl-1,2,4,5-tetrazine.
18 . The method of claim 1 , wherein X is iodine.
19 . The method of claim 1 , wherein LG is −OMs.
20 . The method of claim 1 , wherein L 1 and L 2 are independently substituted or unsubstituted C 1 -C 6 alkylene.
21 . The method of claim 1 , further comprising synthesizing a compound of Formula IV:
by reacting the compound of Formula I with a compound of Formula V:
wherein:
L 3 is a bond or covalent linker; and
R 4 is a biomolecule, a dye or fluorophore.
22 . The method of claim 21 , wherein L 3 is substituted or unsubstituted C 1 -C 6 alkylene.
23 . The method of claim 1 , wherein the dye is a xanthene dye or a boron-dipyrromethene dye.
24 . A compound of Formula I:
wherein:
L 1 and L 2 are independently a bond or linker;
R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a biomolecule, a dye or fluorophore; and
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl or a biomolecule, a dye or fluorophore.
25 . The compound of claim 24 , wherein L 1 and L 2 are independently a bond.
26 . The compound of claim 25 , wherein R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
27 . The compound of claim 25 , wherein R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
28 . The compound of claim 25 , wherein the compound is:
29 . A compound of Formula IV:
wherein:
L 2 and L 3 are independently a bond or linker;
R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or a biomolecule, a dye or fluorophore; and
R 4 is a biomolecule, a dye or fluorophore.
30 . A method of detecting a biomolecule of interest, comprising:
(i) contacting the compound of Formula I of claim 23 , wherein R 2 is a fluorophore, with a compound of Formula V:
wherein:
L 3 is a covalent bond or linker; and R 4 is the biomolecule; and
(ii) detecting the level of fluorescence, wherein an increase in fluorescence compared to a control is indicative of the presence of the biomolecule.
31 . The method of claim 30 , wherein the biomolecule is in a cell.
32 . The method of claim 31 , wherein the cell is a live cell.
33 . The method of claim 31 , wherein the cell is a human cell.
34 . The method of claim 30 , wherein the biomolecule is a lipid, nucleic acid, protein or carbohydrate.
35 . The method of claim 30 , wherein the biomolecule is a phospholipid or antibody.Join the waitlist — get patent alerts
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